**Conflict of interest**

*Current Topics in Biochemical Engineering*

tor as aggregate [21, 106–108].

therapy applications [21].

and there are a very few reports available.

**4. Concluding remarks and future directions**

turing for cell therapy applications.

**Acknowledgements**

and revised the manuscript.

microcarrier is troublesome for clinical application because it needs an extra step for microcarrier separation from the final cell harvest. On the other hand, aggregate culture in bioreactors may not necessarily need a detachment step for harvesting [21–25] and clinically relevant numbers of cells can be produced in a single bioreac-

A major drawback in aggregate culture is the size limitation. With the increase in aggregate size, the growth potential decreases in the large size aggregate due to diffusion limitation of oxygen and nutrients [109]. Therefore, maintaining aggregate size is an important issue to maintain high growth rate as well as high quality for cell

After expansion, cells can be differentiated in the same vessel which makes bioreactor culture a unique choice for integrated biologics manufacturing.

Bioreactors were used for differentiation of hPSCs into various cell types, especially for cardiac [110–112], hepatic [113, 114], and neural [115] lineages. To provide straightforward methods for clinical applications, integration of expansion and differentiation is important and there are several reports published recently where expansion and differentiation were integrated [108, 116–118]. However, the integration of derivation with expansion and differentiation is still facing complications

Steiner et al. reported integration of derivation, propagation and differentiation of hESCs in suspension culture where hESCs were isolated from the inner cell mass in suspension culture that did not involve feeder cells or microcarriers [119]. However, the integration of derivation, expansion, and differentiation is not still realized for personalized medicine especially for autologous or allogenic cell therapy applications. Such integration is needed for overcoming the multi-step cell processing, which will reduce the risk of contamination and save cell processing time as well as reduce manufacturing costs for cell therapy manufacturing.

Cell therapy applications utilizing stem cells are increasing day by day and several clinical trials are ongoing to treat incurable diseases. With the growing need for cell-based products, the manufacturing facilities should be compatible for fulfilling the market demand by supplying safe and effective cell-based products. Since the current manufacturing systems are stuck with several drawbacks, especially multistep processing which poses high risk of contamination as well as long processing time which contributes to increase culture cost, a more straightforward system is required. Bioreactor-based cell manufacturing system can provide a single-step and straightforward processing of cell-based products. Integration of different steps, especially genetic modifications, derivation, and expansion as well as differentiation in bioreactor will pave the future of manufacturing cell-based products. The integrated biologics manufacturing in stirred suspension culture will significantly reduce the risk of contamination of final products, increase product efficacy, and reduce cell processing time and provide a cost-effective platform for cell manufac-

SCN conceptualized, designed, and wrote the manuscript. DER conceptualized

**78**

The authors declare no conflict of interest.
